3-(3-hydroxy-3-phenyl-butylamino) propiophenones



United States Patent 3,525,771 3-(3-HYDROXY-3- HENYL-BUTYLAMINO)PROPIOPHENONES Nicholas Malatestinic, Brooklyn, N.Y., and AlbertZiering, Nutley, N..J., assignors to Hotfmann-La Roche Inc., Nutley,N.J., a corporation of New Jersey No Drawing. Original application Sept.9, 1964, Ser. No. 395,329, now Patent No. 3,337,546, dated Aug. 22,1967. Divided and this application June 23, 1967, Ser. No. 648,208

Int. U. A61k 27/00; C07c 95/00 U.S. El. 260-5705 3 Claims ABSTRACT OFTHE DISCLOSURE 3 (3-hydroxy 3-phenyl butylamino) propiophenone andanalogs thereof are prepared by acid hydrolysis of the corresponding 3(3,4,5,6-tetrahydro-2H-1,3oxazin- B-yl) propiophenones. The novelpropiophenone derivatives have hypotensive properties.

RELATED APPLICATIONS The present application is a division of copendingapplication Ser. No. 395,329, filed Sept. 9, 1964 now U.S. Pat. No.3,337,546.

DETAILED DESCRIPTION OF THE INVENTION 4 R 5 arr-ornam-x-Q wherein thesymbols R represent hydrogen, halogen, lower alkyl, lower alkoxy,hydroxy, nitro or acetamido; R represents hydrogen or lower alkyl; and Xrepresents the carbonyl group or a carbinol group in which the symbol Rrepresents hydrogen or lower alkyl and acid addition salts thereof withpharmaceutically acceptable acids.

Compounds represented by structural Formula I above wherein X is acarbonyl group and R is hydrogen or methyl constitute a preferred group.

In another aspect, the present invention concerns the 3,525,771 PatentedAug. 25, 1970 acid hydrolysis products of the propiophenones of FormulaI and the derivatives thereof which can be represented by the generalformula wherein the symbols R, R and X have the same meaning as aboveand R represents hydrogen or lower alkyl and acid addition salts thereofwith pharmaceutically acceptable acids.

In the formulae above, either one or all of the symbols R may representhydrogen or one of the enumerated substituent groups so that either anunsubstituted phenyl group or a phenyl radical bearing one or moresubstituent groups may be present at the terminal ends of the structure.All four halogens, i.e. chlorine, bromine, fluorine and iodine areincluded Within the meaning of the symbol R. The lower alkyl groupscomprehended by this disclosure are those having 1 to 7 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyland the like. The lower alkoxy groups include ether groups containingthe same lower alkyl radicals as above.

The novel compounds of this invention and their pharmaceuticallyacceptable acid addition salts, i.e., the compounds of Formula I and thecompounds of Formula II and acid salts thereof, have usefulpharmacological properties. Particularly, they are useful as hypotensiveagents, for example, the compounds of Formula I have demonstrated potenthypotensive properties following both intravenous and oraladministration to test animals. More particularly, they are useful inimproving circulation by peripheral vasodilation. Hence, they are usefulin the treatment of hypertension. The compounds of Formula II have alsoshown potent hypotensive properties in test animals, particularlyfollowing intravenous administra tion.

The compounds of the invention can be administered orally orintravenously with dosage adjusted to individual requirements. They canbe administered in conventional pharmaceutical forms, for example, theycan be administered in admixture with conventional organic or inorganicpharmaceutical carriers suitable for oral or intravenous administrationsuch as gelatin, starch, magnesium stearate, talc, vegetable oils, gums,polyethylene glycols, Vaselines and the like. The pharmaceuticalpreparations can be in conventional solid forms such as tablets,dragees, suppositories, capsules, and the like or in conventional liquidforms such as suspensions, emulsions and the like. They can be submittedto conventional pharmaceutical expedients, for example, sterilization,and they can contain pharmaceutical adjuvants such as preservatives,sterilizing agents, wetting agents, emulsifying agents, etc. Thepharmaceutical preparations can also contain other therapeuticallyvaluable substances.

The ketones of structural Formula I above are derived from acetophenonesor substituted acetophenones which can be represented by the formula R 0ll wherein the symbol R has the same significance as in Formulae I andII above by reacting an acetophenone of Formula III with formaldehydeand a substituted oxazine of the general formula in which the symbols Rand R have the same meaning as the corresponding symbols in structuralFormulae I and II above.

The resulting ketones can then be reduced to the corre spondingalcohols. Alternatively, the ketones can be hydrolyzed to the open chaincompounds of Formula II which can in turn be reduced to thecorresponding dihydroxy compounds. The oxazine compounds of Formula IVused as starting materials in the practice of this invention are knowncompounds made by known processes.

The first step of the procedure for forming the products of thisinvention involves reacting paraformaldehyde and an acetophenone or theappropriately substituted acetophenone with an appropriately substitutedoxazine compound of Formula IV, preferabl in the form of itshydrochloride salt. The reaction is suitably carried out by initiallyconverting the oxazine compound to its hydrochloride salt. This can beeasily done by treating the oxazine compound with hydrogen chloride inan inert organic solvent such as ethyl acetate. Preferably, the hydrogenchloride is employed in excess of the amounts theoretically indicated.The reaction of the oxazine salt with the acetophenone is readilycarried out by simply mixing acetophenone and paraformaldehyde with theoxazine salt in a suitable inert organic solvent. As solvents one canuse, for example, hydrocarbon esters such as ethyl acetate, ethylpropionate and the like. The reaction can be carried out over a widerange of temperatures. A convenient temperature is the boiling point ofthe reaction mixture though lower, temperatures can be utilized. Thereaction is completed when all of the oxazine salt has dissolved. Uponcompletion of the reaction, the solution is filtered and concentrateduntil the product crystallizes out. Generally, a well-crystallizedmaterial results which can be easily separated. The product can, ifdesired, be further purified by recrystallizing from a suitable organicsolvent such as acetonitrile or ethyl acetate containing hydrogenchloride gas. The temperature of the reaction is not particularlycritical and for the most part can be varied within wide limits.However, it has been found convenient to operate at an elevatedtemperature. An.

especially suitable temperature is the boiling point of the reactionmixture.

In a next step in the procedure of this invention, the substitutedpropiophenones of Formula I can be converted to the corresponding openchain compounds of Formula II by hydrolysis. The hydrolysis can beconveniently carried out by contacting the substituted propiophenonecompound of Formula I with a molar quantity of water in the presence ofan anhydrous organic solvent. Among the various solvents suitable forthe purpose may be mentioned the low-boiling alcohols such as isobutylalcohol. While the hydrolysis can be carried out with equimolar amountsof reactants, it is preferable to employ a slight excess of water inorder to insure maximum conversion of the substituted propiophenone. Thetemperature of the hydrolysis is not critical and the reaction can becarried out even at room temperature. It has been found convenient,however, to carry out the hydrolysis at the reflux temperature of thereaction mixture. The products are recovered by cooling the hydrolysismixture in ice-water and filtering off the product. The product can befurther purified, if necessary, by recrystallizing from acetonitrile orethyl acetate.

The propiophenone of Formula I can, if desired, be converted to thecorresponding quaternary ammonium salts by the usual method of formingquaternary ammonium salts from tertiary amines. Thus, the propiophenonesof Formula I can be reacted with an alkyl halide, preferably a loweralkyl halide, to obtain the corresponding quaternary ammonium salt whichcan in turn be hydrolyzed in the same manner as above to form theN-alkylated carbinols of Formula II.

The substituted propiophenones of Formula I and Formula II can behydrogenated to produce the corresponding secondary alcohols, forexample, by treating with alkali metal hydrides such as potassiumborohydride, preferably in an inert organic solvent such as alcohol.Other techniques commonly used for reducing carbonyl compounds such ascatalytic reduction with Raney nickel in the presence of alkali couldalso be utilized to convert the carbonyl compounds to the correspondingcarbinols. The substituted propiophenones of Formula I and Formula IIcan also be converted to the tertiary carbinols of this invention byGrignard reaction of the carbonyl radi cal with lower alkyl magnesiumhalides. The Grignard reaction can be carried out in the usual Way byadding the carbonyl compound to the Grignard reagent in ether withstirring. The mixture is then treated with ammonium chloride and theproduct is recovered by distillation.

As indicated above, the products of the invention occur in both the freebase and the acid salt form. The products, as represented by Formula Iand Formula II are in their free base form. In some instances, it willbe desirable to obtain the acid salt from the free base. In this case,the salt can be prepared by reacting the free base with thecorresponding acid in the presence of a suitable organic solvent inwhich theintended salt is insoluble, thereby permitting isolation of thesalt by filtration, decantation or other suitable means. In this way, itis possible to obtain such acid addition salts as the hydrohalides,e.g., hydrochloride, hydrobromide, other mineral acid salts such assulfate, nitrate, phosphate and the like as well as organic acid saltssuch as acetate, tartrate maleate, citrate, salicylate, ascorbate, etc.On the other hand, in those instances where it is desired to convert theacid salt to the free base, the same can be accomplished by dissolvingor suspending the salt in a suitable solvent such as water, methanol,etc., and neutralizing the solution with a basic material such as adilute solution of sodium carbonate, sodium hydroxide, ammoniumhydroxide and the like and isolating the desired base by extraction withether or other similar means. Pharmaceutically acceptable acid additionsalts are prepared from pharmaceutically acceptable acids.

Within the class of compounds represented by Formula I and Formula IIabove those wherein X represents the carbonyl radical constitute apreferred group. Especially preferred compounds of this group are thecompound of Formula I wherein R is hydrogen and R is methyl, namely,3-(3,4,5,6-tetrahydro-6-methyl-6-phenyl-2H 1,3 oxazin-3-yl)propiophenoneand the compound of Formula II wherein R is hydrogen, R is methyl and Ris hydrogen, namely, 3-(3-hydroxy-3-phenylbutylamino)propiophenone.

The examples below illustrate, in detail, some of the compounds whichcomprise this invention and methods for their synthesis. However, theinvention is not to be construed as limited by the examples. Alltemperatures are in degrees centigrade and all melting points arecorrected.

Example 1 .3- 3,4,5 ,6-tetrahydro-6-methyl-6-phenyl-2H- 1,3-oxazin-3-yl) propiophenone hydrochloride A solution of 1.8 g. of3,4,5,6-tetrahydro-6-methyl-6- phenyl-2H-1,3-oxazine in 250 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then 1.4 g. of acetophenone and 3.8 g. of paraformaldehydewere added and the mixture boiled in an open flask until the oxazinesalt had dissolved. The solution was filtered and concentrated until theproduct started to crystallize out. The product was recrystallized fromacetonitrile and melted at 158-160".

Example 2.-3-(3,4,5,6-tetrahydro-6-methyl-6-phenyl-2H- 1,3-oxazin-3 -yl)propiophenone 3 g. of the 3-(6-methyl-6-phenyl-3,4,5,6-tetrahydro-ZH-l,3-oxazin-3-yl)propiophenone hydrochloride was suspended in 20 ml.of water and a dilute solution of sodium carbonate added until the pH ofthe solution was 10. The oil that separated was extracted with ether andthe solution dried over anhydrous potassium carbonate for four hours.Then the ether solution was filtered and the ether distilled ofl. Theresidue, 3-(6-methyl-6-phenyl-3,4,5,6-tetrahydro-2H-l,3-oxazin-3-yl)propiophenone, was a clear oil.

Example 3.--3'-nitro-3-(3,4,5,6-tetrahydro-6 methyl 6- phenyl2H1,3-oxazin-3-yl)propiophenone hydrochloride A solution of 3.5 g. of3,4,5,6-tetrahydro-6-methyl-6- phenyl-2H-l,3-oxazine in 300 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 3.3 g. of rn-nitroacetophenone and 8 g. ofparaformaldehyde were added and the mixture boiled in an open flaslcuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from alcohol and melted at 156-15 8.

Example 5.-4-fluoro-3(3,4,5,6-tetrahydro-6 methyl-6- phenyl-2H-l,3oxazin 3 yl)propiophenone hydrochloride A solution of 3.5 g. of3,4,5,6-tetrahydro-6-methyl-6- phenyl-2H-l,3-oxazine in 300 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 2.6 g. of p-fluoroacetophenone and 8 g. ofparaforrnaldehyde were added and the mixture boiled in an open flaskuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from alcohol and melted at 173-175.

Example 6.--l'-hromo-3-(3,4,5,6-tetrahydro 6- methyl- 6 phenyl 2H 1,3oxazin-3 y1)prop1ophenone hydrochloride A solution of 3.5 g. of3,4,5,6-tetrahydro-6methyl-6- phenyl-2H-l,3-oxazin e in 300 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 4 g. of p-bromoacetophenone and 8 g. of paraformaldehydewere added and the mixture boiled in an open flask until the oxazinesalt had dissolved. The solution was filtered and concentrated until theproduct started to crystallize out. The product was recrystallized fromalcohol and melted at l75-177.

Example 7.4' chloro 3 (3,4,5,6 tetrahydro 6- methyl 6 phenyl 2H 1,3oxazin 3 yl)propiophenone hydrochloride A solution of 3.5 g. of3,4,5,6-tetrahydro-6-methyl-6- phenyl-2H-l,3-oxazine in 300 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 3.1 g. of p-chloroacetophenone and 8 g. ofparaformaldehyde were added and the mixture boiled lllt an open flaskuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product 6 started to crystallize out. The productwas recrystallized from alcohol and melted at 173-175.

Example 8.-4' hydroxy 3 (3,4,5,6 tetrahydro 6- methyl 6 phenyl 2H 1,3oxazin 3 yl)propiophenone hydrochloride A solution of 3.5 g. of3,4,5,6-tetrahydro-6-methyl-6- phenyl-2H-l,3-oxazine in 300 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 2.7 g. of p-hydroxyacetophenone and 8 g. ofparaformaldehyde were added and the mixture boiled in an open flaskuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from alcohol, IVLP. 174-176".

Example 9.4 methoxy 3 (3,4,5,6 tetrahydro 6- methyl 6 phenyl 2H 1,3oxazin 3 yl)propiophenone hydrochloride A solution of 1.8 g. of3,4,5,6-tetrahydro-6-methyl-6- phenyl-2H-1,3oxazine in 250 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 1.5 g. of p-methoxyacetophenone and 8 g. ofparaformaldehyde were added and the mixture boiled in an open flaskuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from alcohol and melted at 162-163.

Example 10.-4' methyl 3 (3,4,5,6 tetrahydro 6- methyl 6 phenyl 2H 1,3oxazin 3 yl)propiophenone hydrochloride A solution of 3.5 g. of3,4,5,6-tetrahydro6-methyl-6- phenyl-2H-l,3-oxazine in 300 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 2.7 g. of p-methylacetophenone and 8 g. ofparaformaldehyde were added and the mixture boiled in an open flaskuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from alcohol and melted at 195-197".

Example ll.-4. acetamido 3 (3,4,5,6 tetrahydro 6 methyl 6 phenyl 2H 1,3oxazin 3 yl) propiophenone hydrochloride A solution of 7.5 g. of3,4,5,6-tetrahydro6-methyl-6- phenyl-2H-l,3-oxazine in 400 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 7.5 g. of p-acetamidoacetophenone and 15 g. ofparaformaldehyde were added and the mixture boiled in an open flaskuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from methanol and melted at 187l89.

Example 12.3',4 dimethoxy 3 (3,4,5,6 tetrahydro 6 methyl 6 phenyl 2H 1,3oxazin 3- yl)propiophenone hydrochloride A solution of 3.5 g. of3,4,5,6-tetrahydro-6-methyl-6- phenyl-2H-l,3-oxazine in 300 ml. of ethylacetate was converted to the hydrochloride with excess hydrogenchloride. Then, 3.6 g. of 3,4-dimethoxyacetophenone and 8 g. ofparat'ormaldehyde were added and the mixture boiled in an open flaskuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from acetonitrile and melted at 177-178".

Example 13.-5,6-dihydro-6-methyl-tx,6-diphenyl 2H-1, 3-oxazine-3 (4H-propanol One gram of potassium borohydride was added in portions to asolution of 5 g. of 3-(3,4,5,6-tetrahydro 6-methyl-6-phenyl-2H-1,3-oxazin-3 yl)propiophenone hydrochloride(Example 1) in ml. of alcohol. The reaction was worked up in the usualway. The product distilled at 190/ .2 mm. After 3 hours stirring at roomtemperature, the alcohol was distilled off in vacuo, water added to theresidue and the oil extracted with ether.

Example 14.4-nitro-3-(3,4,5,6-tetrahydro 6-phenyl-2H-1,3-oxazin-3-yl)propiophenone hydrochloride A mixture of 2 g. of3,4,5,6-tetrahydro-6-phenyl-2H- 1,3-oxazine hydrochloride, 1.7 g. ofp-nitroacetophenone and 4 g. of paraformaldehyde in 250 ml. of ethylacetate containing excess hydrogen chloride was boiled in an open flaskuntil the oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from alcohol and melted at 163-165 Example 15 .3-(3,4,5 ,6-tetrahydro-6 phenyl-2H 1,3-

oxazin-3-yl propiophenone hydrochloride A mixture of3,4,5,6-tetrahydro-6-phenyl-2H-1,3-oxazine hydrochloride, 1.5 g. ofacetophenone and 4 g. of paraformaldehyde in 250 ml. of ethyl acetatecontaining excess hydrogen chloride was boiled in an open flask untilthe oxazine salt had dissolved. The solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from ethyl acetate and melted at 154-155".

Example l6.3-(3-hydroxy-3 phenylbutylamino)propiophenone hydrochloride Asolution of 17.25 g. of 3-(3,4,5,6-tetrahydro-6- methyl-6-phenyl-2H-1,3oxazin-3-yl)propiophenone hydrochloride in 100 ml. of i-butyl alcoholcontaining .9 g. of water, was refluxed for 4 hours. The solution wasthen cooled in ice water and the product filtered off. The productmelted at 172-175". After recrystallization from acetonitrile, theproduct melted at 173-175 Example 17.3-(3-hydroxy-3phenylbutylmethylamino) propiophenone hydrochloride A solution of 25 g.of the methobromide of 3-(3,4,5, 6-tetrahydro-6-methyl-6-phenyl2H-1,3-oxazin 3-yl) propiophenone in 100 ml. of i-butyl alcohol,containing 1.2 ml. of water, was refluxed for 3 hours. The solvent wasdistilled off in vacuo and dilute sodium hydroxide added to the residue.The oil was extracted with chloroform and the solvent distilled off. Theresidue was dissolved in ethyl acetate and the hydrochloride saltprecipitated in the usual way by the addition of hydrogen chloride inethyl acetate. The product was recrystallized from acetonitrile andmelted at 135-137 Example 1 8 .a,a'-lminodiethylene-a-methyldi [benzylalcohol] oxalate A solution of 4.5 g. of base derived from3-(3-hydroxy-3-phenylbutylamino)propiophenone hydrochloride in 150 ml.of methanol, to which was added /2 teaspoon, i.e., about 3 grams, ofRaney nickel was hydrogenated at a starting pressure of 50 lbs. at roomtemperature. After 1 hour, the solution was filtered and the methanoldistilled Off. The residue was distilled at around 200/ .06 mm. (3 g.).The oxalate salt was formed in the usual way by the addition of asolution of oxalic acid in ether to an ether solution of the distilledproduct and after recrystallization from ethyl acetate, melted at 89-91.

Example 19.3- 3-hydroxy-3-phenylbutylamino -3 4-dimethoxypropiophenonehydrochloride A solution of 8 g. of3',4'-dimethoxy-3-(3,4,5,6-tetrahydro-6-methyl-6 phenyl-2H-1,3oxazin-3-yl)propiophenone hydrochloride in 100 ml. of i-butyl alcohol,containing .36 ml. of water, was refluxed for 3 hours. The solvent Wasdistilled OE and the residue crystallized from acetonitrile. The productmelted at 149-151".

8 Example 20.Bis(3-hydroxy 3 phenylbutyDamine maleate The Grignardreagent methyl magnesium iodide was prepared from 5.7 g. of methyliodide and .97 g. of magnesium in ml. of ether. Then, 3.4 g. of3-(3-hydroxy-3-pheny1butylamino)propiophenone hydrochloride was added inportions and after stirring for 2 hours, the mixture was treated with asaturated solution of ammonium chloride. The ether was separated anddried over potassium carbonate. The ether was distilled ofi and theresidue distilled in vacuo. The product distilled at /.06 mm. Thisdistillate was converted to the maleate salt Which, aftercrystallization from ethyl acetate, melted at 133-135".

Example 21.3-(3,4,5,6 tetrahydro-6,6 diphenyl-ZH- 1,3-oxazin-3-yl)propiophenone hydrochloride 3-benzylaminopropiophenone hydrochloride(27.5 g.) was added in portions to a Grignard solution prepared from 72g. of bromobenzene and 11 g. of magnesium in 1 liter of ether. Thereaction was worked up as in the preceding example to yieldwphenyl-ot-(2-benzylaminoethyl)benzyl alcohol which, aftercrystallization from ethyl acetate, melted at 147-148. Debenzylation inthe usual manner with palladium carbon yielded thewphenyla-(2-aminoethyl)-benzyl alcohol which, after crystallization fromethyl acetate, melted at 139-141".

A solution of 7.5 g. of the a-phenyl-u-(2-aminoethyl) benzyl alcohol in25 ml. of methanol was added to a solution of 6 g. of 37 percentformaldehyde in 20 ml. of methanol and the solution held at roomtemperature overnight. Then the solvent was distilled oif and theresidue dissolved in ethyl acetate. Addition of hydrogen chlorideprecipitated the 3,4,5,6-tetrahydro-6,6-diphenyl-2H- 1,3-oxazinehydrochloride, M.P. 173175, after crystallization from acetonitrile.

The oxazine hydrochloride (7.1 g.) was added to a mixture of 3 g. ofacetophenone and 6 g. of paraformaldehyde in 250 ml. of ethyl acetatecontaining some hydrogen chloride. The mixture was boiled in an openflask until the oxazine salt had dissolved. The solution was filteredand concentrated until the product, 3-(3,4,5,6-tetrahydro- 6,6-diphenyl2H-1,3-oxazin-3-yl)propiophenone hydrochloride started to crystallizeout. The product was filtered and melted at 171172.

Example 22.3'-methyl 3-(3,4,5,6-tetrahydro-6-methyl- 6-phenyl 2H1,3-oxazin-3-yl)propiophenone hydrochloride To a suspension of 4.3 g. of3,4,5,6-tetrahydro-6-methyl- 6-phenyl-2H-l,3-oxazine hydrochloride in300 ml. of ethyl acetate containing excess hydrogen chloride was added2.7 g. of 3'-methylacetophenone and 6 g. of paraformaldehyde. Themixture was boiled in an open flask until the oxazine salt haddissolved, then the solution was filtered and concentrated until theproduct started to crystallize out. The product was recrystallized fromacetonitrile and melted at l7l-173.

Example 23.-2-methyl 3-(3,4,5,6-tetrahydro-6-rnethyl- 6-phenyl2H-l,3-oxazin 3-yl)propiophenone hydrochloride To a suspension of 4.3 g.of 3,4,5,6-tetrahydro-6-methyl- 6-phenyl-2H-1,3-oxazine hydrochloride in30 0 ml. of ethyl acetate containing excess hydrogen chloride was added2.7 g. of 2'-methylacetophenone and 6 g. of paraformaldehyde. Themixture was boiled in an open flask until the oxazine salt haddissolved. Then the solution was filtered and concentrated until theproduct started to crystallize out. The product was recrystallized fromacetonitrile and melted at 159-161 9 Example 24.-3'-chloro3-(3,4,5,6-tetrahydro-6-n1ethyl 6-phenyl ZH-LB-oxazin3-yl)propriophenone hydrochloride To a suspension of 4.3 g. of3,4,5,6-tetrahydro-6-rnethyl- 6-pheny1 2l-I-1,3-oxazine hydrochloride in300 ml. of ethyl acetate containing excess hydrogen chloride was added3.1 g. of 3-chloroacetophenone and 6 g. of para formaldehyde. Themixture was boiled in an open flask until the oxazine salt haddissolved, then the solution was filtered and concentrated until theproduct started to crystallize out. The product was recrystallized fromacetonitrile and melted at 164166.

Example 25.--2-chloro 3-(3,4,5,6-tetrahydro-G-methyl- 6-phenyl2H-1,3-oxazin 3-yl)propiophenone hydrochloride To a suspension of 4.3 g.of 3,4,5,6-tetrahydro6-methyl- 6-phenyl 2H-1,3-oxazine hydrochloride in300 ml. of ethyl acetate containing excess hydrogen chloride was added3.1 g. of 2-chloroacetophenone and 6 g. of paraformaldehyde. The mixturewas boiled in an open flask until the oxazine salt had dissolved, thenthe solution was filtered and concentrated until the product started tocrystallize out. The product was recrystallized from acetonitrile andmelted at 144-146 Example 26.3,4'-dimethyl 3-(3,4,5,6-tetrahydro 6-methyl 6-phenyl 2H 1,3-oxazin 3-yl)propiophe none hydrochloride To asuspension of 4.3 g. of 3,4,5,fi-tetrahydro-fi-methyl- 6-pheny12H-1,3-oxazine hydrochloride in 300 ml. of ethyl acetate containingexcess hydrogen chloride was added 3.1 g. of 3,4-dimethylacetophenoneand 6 g. of paraformaldehyde. The mixture was boiled in an open flaskuntil the oxazine salt had dissolved. Then the solution was filtered andconcentrated until the product started to crystallize out. The productwas recrystallized from ethanol and melted at 177-179".

Example 27.2,4'-dichloro 3-(3,4,5,6-tetrahydro 6- methyl 6-pheny12H-1,3-oxazin 3-yl)propiophenone hydrochloride To a suspension of 4.3 g.of 3,4,5,6-tetrahydro 6- methyl 6-pheny1 2H-1,3-oxazine hydrochloride in300 ml. of ethyl acetate containing excess hydrogen chloride was added3.8 g. of 2,4-dichloroacetophen0ne and 6 g. of paraforrnaldehyde. Themixture was boiled in an open flask until the oxazine salt haddissolved. Then the solution was filtered and concentrated until theproduct started to crystallize out. The product was recrystallized fromacetonitrile and melted at 165-167.

We claim:

10 1. A compound of the formula on R CHzCIIzN-CH2CHzX- l ti 1 3 R R islower alkyl; and R and R are selected from the group consisting ofhydrogen and lower alkyl and pharmaceutically acceptable acid additionsalts thereof.

2. A compound according to claim 1 of the formula wherein R, R and R areas in claim 1 and pharmaceutically acceptable acid addition saltsthereof.

3. The compound of claim 2 which is 3-(3-hydroxy-3-phenyl-butylmethylamino) propionphenone.

References Cited UNITED STATES PATENTS 1,911,332. 5/1933 Warnat 260-57062,774,790 12/1956 Hartough et a1. 260-570.6 3,197,507 7/1965 Freed eta1. 260570.5 3,225,095 12/1965 Thiele 260--570.5

OTHER REFERENCES Tsatsos: Chemical Abstracts, vol. 49, pp. 8856-57(1955).

Wiley: Heterocyclic Compounds, Five and Six Membered Compounds WithNitrogen and Oxygen, pp. 344- 48 (1962).

ROBERT V. HINES, Primary Examiner U.S. Cl. X.R.

